Targeting Inhibitory Cells Such as Tregs and MDSCs in the Tuberculous Granuloma

Parveen, Sadiya; Murphy, John R.; Bishai, William R.

doi:10.1007/978-3-030-56905-1_11

Cited by 2 publications

(4 citation statements)

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“…Myeloid cells, including macrophages and myeloid-derived suppressor cells (MDSCs), are known to play an important role in Mtb containment 14 . Since JHU083 is also known to reprogram myeloid cells and reinforce their host-protective functions in murine cancer models, we investigated the impact of JHU083 administration upon lung myeloid cell populations in the mouse TB model.…”

Section: Resultsmentioning

confidence: 99%

“…for their proliferation, activation, and optimal function 36 . Immunosuppressive cells (such as MDSCs and Tregs) create an artificial local depletion of these amino acids, which adversely affects T-cell proliferation and function 14,37 . For example, immunosuppressive myeloid cells overexpress arginase, scavenging arginine and converting it to ornithine and urea 38 .…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…One such prodrug, JHU083, is orally available and is converted to DON by ubiquitous peptidases and esterases, has fewer side effects, and has shown the ability to enhance T-cell immunity in the tumor microenvironment 8,11 . Since blunted effector T-cell immunity are characteristics of both the cancer microenvironment and the tuberculous granuloma 14 , we hypothesized that JHU083 p. 4 might also enhance effector T-cell immunity by a similar immunometabolic reprogramming mechanism and thereby improve host containment of TB disease progression.…”

Section: Introductionmentioning

confidence: 99%

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Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities againstMycobacterium tuberculosis

Parveen¹,

Shen²,

Lun³

et al. 2023

Preprint

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As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a novel glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomics analysis of lungs from JHU083-treated Mtb-infected mice revealed reduced glutamine levels, citrulline accumulation suggesting elevated NOS activity, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. When tested in an immunocompromised mouse model of Mtb infection, JHU083 lost its therapeutic efficacy suggesting the drug host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities againstMycobacterium tuberculosis

Parveen¹,

Shen²,

Lun³

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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Role of glutamine metabolism in tuberculosis pathogenesis: a mini review

Parveen,

Bishai

2024

Front. Tuberc

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Mycobacterium tuberculosis (Mtb) has remained one of the major infectious disease killers for generations and generations. In 2023 alone, this ancient disease was responsible for the death of 1.4 million individuals and has infected 10.6 million people. With the ever-evolving multi- and extremely resistant Mtb strains, the need for novel and effective drugs requiring shorter treatment regimens represents an urgent medical need for the development of new drugs. Over the last two decades, the field of host-directed therapy as a potential novel avenue for new approaches to TB treatment, either as a mono or adjuvant therapy, has garnered increasing attention. Among many host-directed targets, host immunometabolism has emerged as one of the most attractive targets for developing new host-directed therapies. As one of the most successful bacterial pathogens, Mtb has evolved several mechanisms to modulate numerous host metabolic pathways, including glycolysis, glutaminolysis, Kreb cycle, and oxidative phosphorylation. This mini review will focus on glutamine metabolism and its emergence as a potential target for treating tuberculosis (TB). In the last several decades, the role of glutamine metabolism in cancer and neurological disorders has been extensively studied. However, the association of glutamine metabolism with infectious disease has remained underappreciated. The aim of this review is to not only discuss the current knowledge in the field but also the existing knowledge gap that needs further exploration.

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Targeting Inhibitory Cells Such as Tregs and MDSCs in the Tuberculous Granuloma

Cited by 2 publications

References 232 publications

Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities againstMycobacterium tuberculosis

Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities againstMycobacterium tuberculosis

Role of glutamine metabolism in tuberculosis pathogenesis: a mini review

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